The present invention is generally in the area of targeting and regulation of expression of recombinant gene constructs incorporating regulatory elements present in the promoter of an endothelial cell protein C/activated protein C receptor.
Atherosclerosis and most other vascular disease primarily occur in large vessels. Endothelial cells are a primary defense mechanism against cellular infiltration and thrombosis. Abnormal function of the endothelial cells contribute to myocardial infarction (MI), stroke and the development of atherosclerotic plaque. The delivery of proteins or protein expression inhibitors, directly or via gene therapy, specific to large vessel endothelial cells, is one means for addressing these clinical conditions. For example, the anti-thrombotic potential of endothelium can be increased by delivering agents that prevent thrombosis, such as thrombomodulin, heparin proteoglycans, tissue factor pathway inhibitor (TFPI, a potent inhibitor of the tissue Factor-Factor VIIa-Factor Xa complex), etc. Fibrinolytic activity can be increased by overexpression of tissue plasminogen activator (tPA) or urokinase. Expression of adhesion molecules such as P-selectin or ICAMs can be inhibited to minimize or decrease the probability of atherosclerotic plaque rupture.
Targeting endothelial cells non-specifically is often inadequate. Since more than 95% of endothelial cells are in the capillaries, any therapy directed toward endothelial cells per se runs the risk of systemic complications. One must be confident that the gene expression is limited to the desired cells when using a gene therapy approach.
It is therefore an object of the present invention to provide means and methods for selective expression of genes, especially in endothelial cells, and even more specifically in large vessel endothelial cells.
It is a further object of the present invention to provide means and methods for selective expression of genes in response to specific stimuli.